The present invention relates to new compounds which are derivatives of indole, pharmaceutical formulations containing them, and use of the compounds in the manufacture of medicaments for treating various diseases.
The novel compounds described herein are structurally and functionally related to melatonin, 3-2-acetaminoethyl)-5-methoxyindole, a hormone produced primarily by the pineal gland. Melatonin is the principal hormone secreted by the pineal gland in all vertebrates. In all mammals studied to date, including humans, a nocturnal rise in the production of melatonin by the pineal gland is evident; melatonin production by the body is acutely suppressed by light. Melatonin is involved in the coordination of photoperiod dependent and physiological processes. The ability of the animals or humans to respond to the melatonin signal may depend upon melatonin receptors. Melatonin acts on the CNS to affect neural mechanisms through receptors located in the brain. Additionally, a number of studies indicate the existence of direct effects of melatonin in peripheral organs via peripheral melatonin receptors. Melatonin receptors are present in the heart, lungs, prostate gland, gonads, white blood cells, retina, pituitary, thyroid, kidney, gut and blood vessels. Retention patterns of radioactive-melatonin injected to rat's demonstrate melatonin accumulation in the brain, pituitary, lung, heart, gonads and accessory sex organs (Withyachumnamkul et al., Life Sci, 12:1757-65, 1986).
The synthesis and secretion of melatonin exhibit a circadian rhythm that changes with the seasons and with age, e.g., pubescence and senescence. There is very strong evidence that melatonin is important for the regulation of a variety of neural and endocrine functions, especially those that exhibit circadian and circannual rhythmicity.
Melatonin has been implicated in many human disorders. Some are known to be linked to chronobiological abnormalities. Melatonin has been administered to re-synchronize circadian rhythms that are out of phase with the local photoperiodical cycle. For example, sleep/wake disorders with rapid crossing of time zones (jet lag), or in delayed sleep phase syndrome (DSPS) patients, changes in work shifts, or those experienced by blind people can be treated with melatonin or melatonin analogs (see U.S. Pat. Nos. 4,600,723 and 4,666,086 of Short et al. and 5,242,941 of Lewy et al.). However, it appears that melatonin also has direct sedative/hypnotic properties in normal human subjects (e.g., Waldhauser et al., Psychopharmacology, 100: 222-226, 1990; Vollrath et al., Bioscience, 29:327-329, 1981; Doilins et al., Proc. Natl. Acad. Sci, 99:1824-1828, 1994; U.S. Pat. No. 5,403,851 of D'Orlando et al). Three melatonin receptor subtypes have been identified so far mt-1, MT-2 and Me11c (Barrett et al., Biol. Signals Recept., 1999, 8: 6-14). MT-2 is localized mainly in the central nervous system and mt-1, is localized in the CNS as well as in peripheral organs such as kidney and the urogenital tract (Dubocovich et a)., IUPHAR media, London, UK, 187-93, 1998). The presently known subtypes are not sufficient to evaluate the large variety of melatonin effects and additional receptor subtypes await discovery.
Melatonin has been demonstrated in a number of rodent experimental paradigms to have both anxiolytic (Golus and King, Pharmacol. Biochem. Behav., 41:405-408, 1992, Naranjo-Rodriguez et al., Soc. Neurosci. Abst., 18:1167, 1992; Golombek et al., Eur. J. Pharmacol, 237:231-236, 1993) and antiseizure activity (Brallowsky, Electroencephalo. Clin. Neurophysiol., 41:314-319, 1976; Fariello et al., Neurology, 27:567-570, 1977; Rudeen et al., Epilepsia, 21:149-154, 1980; Sugden, J. Pharmacol Exp. Ther., 227:587-591, 1983; Golombek et al., Eur. J. Pharmacol, 210:253-258, 1992).
Melatonin is effective in the treatment of cluster headache and migraine (Claustrat et al., Headache, 29:241-4, 1989). Melatonin may play a role in other psychiatric conditions, particularly depression, but also mania and schizophrenia (see Dobocovich, “Antidepressant Agents”; U.S. Pat. No. 5,093,352; Miles and Philbrick, Biol. Psychiatry, 23:405-425, 1988; Sandyk and Kay, Schizophr. Bull., 16:653-662, 1990). In some instance, psychiatric disorders may have underlying chronobiological etiologies (e.g. seasonal effective disorder) and are definite candidates for melatonin therapy.
Melatonin is involved in the regulation of circadian and circannual changes in body temperature. Administration of exogenous melatonin to humans lowers core body temperature (Strassman et al., J. Appl. Physiol, 71:2178-2182, 1991; Cagnacci et al., J. Clin. Endocrinol. Merab., 75:447-452, 1992). Melatonin may also possess analgesic properties (Sugden, J. Pharmacol. Exp. Ther., 227:587-591, 1983). Therefore, melatonin-like compounds may be useful as an alternative to non-steroidal anti-inflammatory, anti-pyretic drugs, such as aspirin, acetaminophen and ibuprofen.
It is known that melatonin levels decrease with advancing age (Sack et al., J. Pineal Res., 4:379-388, 1986; Waldhauser et al., J. Clin. Endocrinol. Metab., 66:648-652, 1988; Van Coavorden et al., Am. J. Physiol., 260:E651-61, 1991) which may contribute to some disorders. Neurodegenerative diseases often associated with aging, such as Alzheimer's and Parkinson's diseases, may be treated with melatoninergic compounds (Maurizi, Med. Hypotheses, 31:233-242, 1990; Sandyk, Int. J. Neurosci., 50:37-53, 1990; Skene et al., Brain Rev., 528:170-174, 1990).
Sleep disorders in the elderly have been shown to respond to melatonin treatment (Garfinkel et al., Lancet, 346:541-543, 1995; U.S. Pat. No. 5,498,423 of Zisapel). Soporific effects of melatonin (0.3-240 mg) have been reported in humans following intravenous, intranasal and oral administration. Apart from its soporific effects, exogenous melatonin may affect sleep via its phase-resetting action on the biological clock. Melatonin administration advanced sleep in delayed sleep syndrome patients, and synchronized sleep to the day-night cycles in blind subjects. The efficacy of melatonin (0.3-5 mg/os) for treatment of insomnia has been demonstrated in studies performed mainly with elderly patients, patients treated with atenolol and chronic heart patients, most of which patients have low or distorted melatonin rhythms. In some of these studies, formulations which release melatonin throughout the night were used, in order to circumvent fast clearance of the hormone and to mimic its endogenous profile (Nutrition, 1998, 14: 1-2; The Aging Male, 1998, 1: 1-8). Melatonin, 3 mg, given to patients with sleep disorders and dementia for 21 days, significantly augmented sleep quality and decreased the number of wakening episodes, while agitated behavior at night (sundowning) decreased significantly (Biol. Signals Recept., 1999, 8(1-2): 126-31).
We have recently found that melatonin treatment may be beneficial not only for improving sleep quality, but may also lead to an improvement in the general state of diabetic patients, as indicated by the decrease in HbA1c levels after long-term treatment.
Daily melatonin supplementation to male Sprague-Dawley rats, starting at middle age (10 months) and continuing into old age (22 months) via the drinking water at a dosage of 4 μg/ml, restored the age-related elevated levels of relative (% of body weight) retroperitoneal and epididymal fat, as well as plasma insulin and leptin levels to youthful (4 month) levels (Rasmussen et al., Endocrinology, 1999, 140(2): 1009-12).
Even osteoporosis may have a melatoninergic component (Sandyk et al., Int. J. Neurosci., 62:215-225, 1992). In fact, melatonin has been suggested to be an anti-aging, anti-stress hormone (Armstrong and Redman, Med. Hypotheses, 34:300-309, 1991; Reiter. Bioassays, 14:169-175, 1992). This may be due to its action as a free radical scavenger (Pooggeler et al., J. Pineal Res, 14:151-168, 1993) or its interaction with the immune system (Maestroni and Conti, J. Neuroimmun., 28:167-176 1990; Fraschini et al., Acta Oncol., 29:775-776 1990; Guerrero and Reiter, Endocr. Res., 18:91-113, 1992). Melatonin may protect from ischemic stroke (Cho et al., Brain Research, 755:339-338, 1997), decrease cell-death in Atzheimer's disease (Pappola et al., J Neurosci, 17:168390, 1997) and lower the risk of SIDS in young infants with low endogenous melatonin levels (Israel Patents Nos. 115861/2 and U.S. Pat. No. 5,500,225 of Laudon et al).
Related to the above are the findings that melatonin has oncostatic properties in a variety of cancers, the most studied being its effect on estrogen receptor positive breast cancers (Blasak and Hill, J. Neural. Transm. Suppl., 21:433-449, 1986; Gonzalez et al., Melanoma. Res.,1:237-243, 1991; Lissoni et al., Eur. J. Cancer, 29A:185-189, 1993, Shellard et al., Br. J. Cancer, 60:288-290, 1989; Philo and Berkowitz, J. Urol., 139:1099-1102, 1988; see U.S. Pat. No. 5,196,435 of Clemens et al. and U.S. Pat. No. 5,272,141 of Fraschini et al.). It is also possible that melatonin has antiproliferative effects on noncancerous cells as well and may be of use to treat benign tumors and proliferative diseases such as BPH (U.S. Pat. No. 5,750,557 and European Patent No. EP 0565296B of Zisapel) and Psoriasis.
A major portion of research on melatonin has been devoted to studying is effects on reproduction, particularly in seasonally breeding species (such as hamsters and sheep), in which melatonin is known to regulate fertility and puberty, hibernation, and coat color. These effects have obvious significance for animal husbandry use. Reproductive endocrine uses in humans for melatonin include: contraceptive and fertility agents, treatment for precocious puberty, treatment for premenstrual syndrome and hyperprolactinemia (Pevre et al., J. Clin. Endocrinol. Metab., 47:1383-1386, 1978; Purry et al., Am. J. Psychiatry, 144:762-766, 1987; Waldhauser et al., Clin. Endocrinol. Metab., 73:793-796, 1991; Bispink et al., Pineal Res., 8:97-106, 1990; Cagnacci et al., J. Clin. Endocrinol. Metab., 73:210-220, 1991; Voordouw et al., J. Clin. Endocrinol. Metab., 74:107-108, 1992, see U.S. Pat. Nos. 4,855,305 and 4,945,103 of Cohen et al.; and U.S. Pat. No. 5,272,141 of Fraschini et al.). It is likely that melatonin compounds may also be useful in other endocrine conditions, particularly those involving growth hormone (Cramer et al., Arzeneim-Forsch, 26:1076-1078,1976; Wright et al., Clin. Endocrinol., 24:375-382, 1986; Paccotti et al., Chronobiologica, 15:279-288, 1988; Valcavi et al., Clin. Endocrinol., 39:139-199, 1993). Melatonin may serve to reduce prostate6 enlargement (see above-cited US and EP patents of Zisapel). Orally administered melatonin to castrated juvenile rats inhibited the androgen-dependent growth of the ventral prostate and the seminal vesicles (Gilad et al., J. of Urol., 159:1069-73, 1998). Recently, we have demonstrated high affinity melatonin receptors in the human benign prostate epithelial cells, which may affect cell growth and viability (Endocrinology, 137:1412-17, 1996).
In addition to the pineal gland, the eye also synthesizes melatonin. Recently melatonin has been implicated in the control of intraocular pressure and may be of use in glaucoma (Samples et al., Curr. Eye Res., 7:649-653, 1988; Rhode et al., Ophthalmic. Res., 25:10-15, 1993).
The kidney also expresses melatonin receptors, and melatonin has been shown to affect vasopressin and urine excretion (Song et al., FASEB J. 11:93-100, 1997; Yasin et al., Brain Res. Bull; 39:1-5, 1997).
It is clear that there exists a broad range of therapeutic uses for melatonin. Accordingly it is of continuing interest to identify novel compounds that interact with melatoninergic systems as potential therapeutic agents. These compounds may offer longer duration, selective localization and greater efficacy to those of melatonin.
Novel compounds related to melatonin, but with pharmacological or pharmacokinetic profiles different from melatonin, are likely to be important new pharmaceuticals. For examples, see U.S. Pat. No. 5,403,851 which discloses the use of substituted tryptamines, phenylalkylamines and related compounds, in order to treat a number of pharmaceutical indications including sleep disorders, endocrine indications, immune-system disorders etc. PCT Patent Application No. WO 87/00432 describes compositions, for treating or preventing psoriasis, which contain melatonin or related compounds. European Patent Application No. 0330625A2 discloses the production of melatonin and analogs thereof, for various therapeutic purposes, including the administration of melatonin in combination with an azidothymidine for the treatment of AIDS. Melatonin analogs based on the bioisosteric properties naphthalenic ring and the indole ring have been disclosed in J. Med. Chem., 1992, 35:1484-1485; EP 662471 A2 950712 of Depreuxi et al.; WO 9529173 A1 951102 of Ladlow et al.; U.S. Pat. Nos. 5,151,446 of Horn et al.; U.S. Pat. No. 5,194,614 of Adrieux et al. and U.S. Pat. No. 5,276,051 of Lesieur et al.
There is evidence suggesting both melatonin agonists and antagonists would be of potential therapeutic use for a variety of maladies and conditions. The present invention addresses the need for more therapeutically selective compounds than melatonin.
The entire contents of the above-cited patents, patent applications and literature articles are deemed to be incorporated herein by reference.